A quantitative in vivo imaging platform for tracking pathological tau depositions and resultant neuronal death in a mouse model

Purpose: Depositions of tau fibrils are implicated in diverse neurodegenerative disorders, including Alzheimer’s disease, and precise assessments of tau pathologies and their impacts on neuronal survival are crucial for pursuing the neurodegenerative tau pathogenesis with and without potential therapies. We aimed to establish an in vivo imaging system to quantify tau accumulations with positron emission tomography (PET) and brain atrophy with volumetric MRI in rTg4510 transgenic mice modeling neurodegenerative tauopathies. Methods: A total of 91 rTg4510 and non-transgenic control mice underwent PET with a tau radiotracer, ¹⁸F-PM-PBB3, and MRI at various ages (1.8–12.3 months). Using the cerebellum as reference, the radiotracer binding in target regions was estimated as standardized uptake value ratio (SUVR) and distribution volume ratio (DVR). Histopathological staining of brain sections derived from scanned animals was also conducted to investigate the imaging-neuropathology correlations. Results: ¹⁸F-PM-PBB3 SUVR at 40–60 min in the neocortex, hippocampus, and striatum of rTg4510 mice agreed with DVR, became significantly different from control values around 4–5 months of age, and progressively and negatively correlated with age and local volumes, respectively. Neocortical SUVR also correlated with the abundance of tau inclusions labeled with PM-PBB3 fluorescence, Gallyas-Braak silver impregnation, and anti-phospho-tau antibodies in postmortem assays. The in vivo and ex vivo ¹⁸F-PM-PBB3 binding was blocked by non-radioactive PM-PBB3. ¹⁸F-PM-PBB3 yielded a 1.6-fold greater dynamic range for tau imaging than its ancestor, ¹¹C-PBB3. Conclusion: Our imaging platform has enabled the quantification of tau depositions and consequent neuronal loss and is potentially applicable to the evaluation of candidate anti-tau and neuroprotective drugs.